Postacute COVID-19 Syndrome: 129Xe MRI Ventilation Defects and Respiratory Outcomes 1 Year Later.

Background In individuals with postacute COVID-19 syndrome (PACS) and normal pulmonary function, xenon 129 (129Xe) MRI ventilation defects, abnormal quality-of-life scores, and exercise limitation were reported 3 months after infection; the longitudinal trajectory remains unclear. Purpose To measure and compare pulmonary function, exercise capacity, quality of life, and 129Xe MRI ventilation defect percent (VDP) in individuals with PACS evaluated 3 and 15 months after COVID-19 infection. Materials and Methods In this prospective study, participants with PACS aged 18-80 years were enrolled between July 2020 and August 2021 from two quaternary care centers. 129Xe MRI VDP, diffusing capacity of lung for carbon monoxide (Dlco), spirometry, oscillometry, 6-minute walk distance (6MWD), and St George Respiratory Questionnaire (SGRQ) scores were evaluated 3 months and 15 months after COVID-19 infection. Differences between time points were evaluated using the paired t test. Multivariable models were generated to explain exercise capacity and quality-of-life improvement. Odds ratios (ORs) were used to evaluate potential treatment influences. Results Overall, 53 participants (mean age, 55 years ± 18 [SD]; 27 women) attended both 3- and 15-month visits and were included in the analysis. The mean values for 129Xe MRI VDP (5.8% and 4.2%; P = .003), forced expiratory volume in the 1st second of expiration percent predicted (84% and 90%; P = .001), Dlco percent predicted (86% and 99%; P = .002), and SGRQ score (35 and 25; P < .001) improved between the 3- and 15-month visit. VDP measured 3 months after COVID-19 infection predicted the change in 6MWD (ß = -0.643, P = .006), while treatment with respiratory medication at 3 months predicted an improved quality-of-life score at 15 months (OR, 4.0; 95% CI: 1.2, 13.8; P = .03). Conclusion Pulmonary function, gas exchange, exercise capacity, quality of life, and 129Xe MRI ventilation defect percent (VDP) improved in participants with postacute COVID-19 syndrome at 15 months compared with 3 months after infection. VDP measured at 3 months after infection correlated with improved exercise capacity, while treatment with respiratory medication was associated with an improved quality-of-life score 15 months after infection. ClinicalTrials.gov registration no. NCT05014516 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Vogel-Claussen in this issue.

Persistent 129Xe MRI Pulmonary and CT Vascular Abnormalities in Symptomatic Individuals with Post-acute COVID-19 Syndrome.

BACKGROUND: In patients with post-acute COVID-19 syndrome (PACS), abnormal gas-transfer and pulmonary vascular density have been reported, but such findings have not been related to each other or to symptoms and exercise limitation. The pathophysiologic drivers of PACS in patients previously infected with COVID-19 who were admitted to in-patient treatment in hospital (or ever-hospitalized patients) and never-hospitalized patients are not well understood. PURPOSE: To determine the relationship of persistent symptoms and exercise limitation with xenon 129 (129Xe) MRI and CT pulmonary vascular measurements in individuals with PACS. MATERIALS AND METHODS: In this prospective study, patients with PACS aged 18-80 years with a positive polymerase chain reaction COVID-19 test were recruited from a quaternary-care COVID-19 clinic between April and October 2021. Participants with PACS underwent spirometry, diffusing capacity of the lung for carbon monoxide (DLco), 129Xe MRI, and chest CT. Healthy controls had no prior history of COVID-19 and underwent spirometry, DLco, and 129Xe MRI. The 129Xe MRI red blood cell (RBC) to alveolar-barrier signal ratio, RBC area under the receiver operating characteristic curve (AUC), CT volume of pulmonary vessels with cross-sectional area 5 mm2 or smaller (BV5), and total blood volume were quantified. St George's Respiratory Questionnaire, International Physical Activity Questionnaire, and modified Borg Dyspnea Scale measured quality of life, exercise limitation, and dyspnea. Differences between groups were compared with use of Welch t-tests or Welch analysis of variance. Relationships were evaluated with use of Pearson (r) and Spearman (ρ) correlations. RESULTS: Forty participants were evaluated, including six controls (mean age ± SD, 35 years ± 15, three women) and 34 participants with PACS (mean age, 53 years ± 13, 18 women), of whom 22 were never hospitalized. The 129Xe MRI RBC:barrier ratio was lower in ever-hospitalized participants (P = .04) compared to controls. BV5 correlated with RBC AUC (ρ = .44, P = .03). The 129Xe MRI RBC:barrier ratio was related to DLco (r = .57, P = .002) and forced expiratory volume in 1 second (ρ = .35, P = .03); RBC AUC was related to dyspnea (ρ = -.35, P = .04) and International Physical Activity Questionnaire score (ρ = .45, P = .02). CONCLUSION: Xenon 129 (129Xe) MRI measurements were lower in participants previously infected with COVID-19 who were admitted to in-patient treatment in hospital with post-acute COVID-19 syndrome, 34 weeks ± 25 after infection compared to controls. The 129Xe MRI measures were associated with CT pulmonary vascular density, diffusing capacity of the lung for carbon monoxide, exercise capacity, and dyspnea. Clinical trial registration no.: NCT04584671 © RSNA, 2022 Online supplemental material is available for this article See also the editorial by Wild and Collier in this issue.

129Xe MRI ventilation defects in ever-hospitalised and never-hospitalised people with post-acute COVID-19 syndrome.

BACKGROUND: Patients often report persistent symptoms beyond the acute infectious phase of COVID-19. Hyperpolarised 129Xe MRI provides a way to directly measure airway functional abnormalities; the clinical relevance of 129Xe MRI ventilation defects in ever-hospitalised and never-hospitalised patients who had COVID-19 has not been ascertained. It remains unclear if persistent symptoms beyond the infectious phase are related to small airways disease and ventilation heterogeneity. Hence, we measured 129Xe MRI ventilation defects, pulmonary function and symptoms in ever-hospitalised and never-hospitalised patients who had COVID-19 with persistent symptoms consistent with post-acute COVID-19 syndrome (PACS). METHODS: Consenting participants with a confirmed diagnosis of PACS completed 129Xe MRI, CT, spirometry, multi-breath inert-gas washout, 6-minute walk test, St. George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) dyspnoea scale, modified Borg scale and International Physical Activity Questionnaire. Consenting ever-COVID volunteers completed 129Xe MRI and pulmonary function tests only. RESULTS: Seventy-six post-COVID and nine never-COVID participants were evaluated. Ventilation defect per cent (VDP) was abnormal and significantly greater in ever-COVID as compared with never-COVID participants (p<0.001) and significantly greater in ever-hospitalised compared with never-hospitalised participants who had COVID-19 (p=0.048), in whom diffusing capacity of the lung for carbon-monoxide (p=0.009) and 6-minute walk distance (6MWD) (p=0.005) were also significantly different. 129Xe MRI VDP was also related to the 6MWD (p=0.02) and post-exertional SpO2 (p=0.002). Participants with abnormal VDP (≥4.3%) had significantly worse 6MWD (p=0.003) and post-exertional SpO2 (p=0.03). CONCLUSION: 129Xe MRI VDP was significantly worse in ever-hospitalised as compared with never-hospitalised participants and was related to 6MWD and exertional SpO2 but not SGRQ or mMRC scores. TRIAL REGISTRATION NUMBER: NCT05014516.

Protocols for multi-site trials using hyperpolarized 129 Xe MRI for imaging of ventilation, alveolar-airspace size, and gas exchange: A position paper from the 129 Xe MRI clinical trials consortium.

Hyperpolarized (HP) 129 Xe MRI uniquely images pulmonary ventilation, gas exchange, and terminal airway morphology rapidly and safely, providing novel information not possible using conventional imaging modalities or pulmonary function tests. As such, there is mounting interest in expanding the use of biomarkers derived from HP 129 Xe MRI as outcome measures in multi-site clinical trials across a range of pulmonary disorders. Until recently, HP 129 Xe MRI techniques have been developed largely independently at a limited number of academic centers, without harmonizing acquisition strategies. To promote uniformity and adoption of HP 129 Xe MRI more widely in translational research, multi-site trials, and ultimately clinical practice, this position paper from the 129 Xe MRI Clinical Trials Consortium (https://cpir.cchmc.org/XeMRICTC) recommends standard protocols to harmonize methods for image acquisition in HP 129 Xe MRI. Recommendations are described for the most common HP gas MRI techniques-calibration, ventilation, alveolar-airspace size, and gas exchange-across MRI scanner manufacturers most used for this application. Moreover, recommendations are described for 129 Xe dose volumes and breath-hold standardization to further foster consistency of imaging studies. The intention is that sites with HP 129 Xe MRI capabilities can readily implement these methods to obtain consistent high-quality images that provide regional insight into lung structure and function. While this document represents consensus at a snapshot in time, a roadmap for technical developments is provided that will further increase image quality and efficiency. These standardized dosing and imaging protocols will facilitate the wider adoption of HP 129 Xe MRI for multi-site pulmonary research.

Hyperpolarized 129 Xe imaging of embryonic stem cell-derived alveolar-like macrophages in rat lungs: proof-of-concept study using superparamagnetic iron oxide nanoparticles.

PURPOSE: To measure regional changes in hyperpolarized 129 Xe MRI signal and apparent transverse relaxation ( T2∗ ) because of instillation of SPION-labeled alveolar-like macrophages (ALMs) in the lungs of rats and compare to histology. METHODS: MRI was performed in 6 healthy mechanically ventilated rats before instillation, as well as 5 min and 1 h after instillation of 4 million SPION-labeled ALMs into either the left or right lung. T2∗ maps were calculated from 2D multi-echo data at each time point and changes in T2∗ were measured and compared to control rats receiving 4 million unlabeled ALMs. Histology of the ex vivo lungs was used to compare the regional MRI findings with the locations of the SPION-labeled ALMs. RESULTS: Regions of signal loss were observed immediately after instillation of unlabeled and SPION-labeled ALMs and persisted at least 1 h in the case of the SPION-labeled ALMs. This was reflected in the measurements of T2∗ . One hour after the instillation of SPION-labeled ALMs, the T2∗ decreased to 54.0 ± 7.0% of the baseline, compared to a full recovery to baseline after the instillation of unlabeled ALMs. Histology confirmed the co-localization of SPION-labeled ALMs with regions of signal loss and T2∗ decreases for each rat. CONCLUSION: Hyperpolarized 129 Xe MRI can detect the presence of SPION-labeled ALMs in the airways 1 h after instillation. This approach is promising for targeting and tracking of stem cells for the treatment of lung disease.

High spatial resolution hyperpolarized 3 He MRI of the rodent lung using a single breath X-centric gradient-recalled echo approach.

PURPOSE: Hyperpolarized (HP) gas MRI of the rodent lung is of great interest because of the increasing need for novel biomarkers with which to develop new therapies for respiratory diseases. The use of fast gradient-recalled echo (FGRE) for high-resolution HP gas rodent lung MRI is challenging as a result of signal loss caused by significant diffusion weighting, particularly in the larger airways. In this work, a modified FGRE approach is described for HP 3 He rodent lung MRI using a centric-out readout scheme (ie, x-centric), allowing high-resolution, density-weighted imaging. METHODS: HP 3 He x-centric imaging was performed in a phantom and compared with a conventional partial-echo FGRE acquisition for in-plane spatial resolutions varying between 39 and 312 µm. Partial-echo and x-centric acquisitions were also compared for high spatial-resolution breath-hold (1 s) imaging of rodent lungs. RESULTS: X-centric provided improved signal-to-noise ratio efficiency by a factor of up to 13/1.7 and 6.7/1.8, compared with the partial-echo FGRE for the airways/parenchyma of mouse and rat, respectively, at high spatial resolutions in vivo (<78 µm). In particular, rodent major airways with less restricted diffusion of 3 He could only be visualized with the x-centric method. CONCLUSIONS: The x-centric method significantly reduces diffusion weighting, allowing high spatial and temporal resolution HP 3 He gas density-weighted rodent lung MRI. Magn Reson Med 78:2334-2341, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Quantification of regional early stage gas exchange changes using hyperpolarized (129)Xe MRI in a rat model of radiation-induced lung injury.

PURPOSE: To assess the feasibility of hyperpolarized (HP) (129)Xe MRI for detection of early stage radiation-induced lung injury (RILI) in a rat model involving unilateral irradiation by assessing differences in gas exchange dynamics between irradiated and unirradiated lungs. METHODS: The dynamics of gas exchange between alveolar air space and pulmonary tissue (PT), PT and red blood cells (RBCs) was measured using single-shot spiral iterative decomposition of water and fat with echo asymmetry and least-squares estimation images of the right and left lungs of two age-matched cohorts of Sprague Dawley rats. The first cohort (n = 5) received 18 Gy irradiation to the right lung using a (60)Co source and the second cohort (n = 5) was not irradiated and served as the healthy control. Both groups were imaged two weeks following irradiation when radiation pneumonitis (RP) was expected to be present. The gas exchange data were fit to a theoretical gas exchange model to extract measurements of pulmonary tissue thickness (LPT) and relative blood volume (VRBC) from each of the right and left lungs of both cohorts. Following imaging, lung specimens were retrieved and percent tissue area (PTA) was assessed histologically to confirm RP and correlate with MRI measurements. RESULTS: Statistically significant differences in LPT and VRBC were observed between the irradiated and non-irradiated cohorts. In particular, LPT of the right and left lungs was increased approximately 8.2% and 5.0% respectively in the irradiated cohort. Additionally, VRBC of the right and left lungs was decreased approximately 36.1% and 11.7% respectively for the irradiated cohort compared to the non-irradiated cohort. PTA measurements in both right and left lungs were increased in the irradiated group compared to the non-irradiated cohort for both the left (P < 0.05) and right lungs (P < 0.01) confirming the presence of RP. PTA measurements also correlated with the MRI measurements for both the non-irradiated (r = 0.79, P < 0.01) and irradiated groups (r = 0.91, P < 0.01). CONCLUSIONS: Regional RILI can be detected two weeks post-irradiation using HP (129)Xe MRI and analysis of gas exchange curves. This approach correlates well with histology and can potentially be used clinically to assess radiation pneumonitis associated with early RILI to improve radiation therapy outcomes.

Early stage radiation-induced lung injury detected using hyperpolarized (129) Xe Morphometry: Proof-of-concept demonstration in a rat model.

PURPOSE: Radiation-induced lung injury (RILI) is still the major dose-limiting toxicity related to lung cancer radiation therapy, and it is difficult to predict and detect patients who are at early risk of severe pneumonitis and fibrosis. The goal of this proof-of-concept preclinical demonstration was to investigate the potential of hyperpolarized (129) Xe diffusion-weighted MRI to detect the lung morphological changes associated with early stage RILI. METHODS: Hyperpolarized (129) Xe MRI was performed using eight different diffusion sensitizations (0.0-115 s/cm(2) ) in a small group of control rats (n = 4) and rats 2 wk after radiation exposure (n = 5). The diffusion-weighted images were used to obtain morphological estimates of the pulmonary parenchyma including external radius (R), internal radius (r), alveolar sleeve depth (h), and mean airspace chord length (Lm ). The histological mean linear intercept (MLI) were obtained for five control and five irradiated animals. RESULTS: Mean R, r, and Lm were both significantly different (P < 0.02) in the irradiated rats (74 ± 17 µm, 43 ± 12 µm, and 54 ± 17 µm, respectively) compared with the control rats (100 ± 12 µm, 67 ± 10 µm, and 79 ± 12 µm, respectively). Changes in measured Lm values were consistent with changes in MLI values observed by histology. CONCLUSIONS: Hyperpolarized (129) Xe MRI provides a way to detect and measure regional microanatomical changes in lung parenchyma in a preclinical model of RILI. Magn Reson Med 75:2421-2431, 2016. © 2015 Wiley Periodicals, Inc.

Hyperpolarized (129) Xe imaging of the rat lung using spiral IDEAL.

PURPOSE: To implement and optimize a single-shot spiral encoding strategy for rapid 2D IDEAL projection imaging of hyperpolarized (Hp) (129) Xe in the gas phase, and in the pulmonary tissue (PT) and red blood cells (RBCs) compartments of the rat lung, respectively. THEORY AND METHODS: A theoretical and experimental point spread function analysis was used to optimize the spiral k-space read-out time in a phantom. Hp (129) Xe IDEAL images from five healthy rats were used to: (i) optimize flip angles by a Bloch equation analysis using measured kinetics of gas exchange and (ii) investigate the feasibility of the approach to characterize the exchange of Hp (129) Xe. RESULTS: A read-out time equal to approximately 1.8 × T2* was found to provide the best trade-off between spatial resolution and signal-to-noise ratio (SNR). Spiral IDEAL approaches that use the entire dissolved phase magnetization should give an SNR improvement of a factor of approximately three compared with Cartesian approaches with similar spatial resolution. The IDEAL strategy allowed imaging of gas, PT, and RBC compartments with sufficient SNR and temporal resolution to permit regional gas exchange measurements in healthy rats. CONCLUSION: Single-shot spiral IDEAL imaging of gas, PT and RBC compartments and gas exchange is feasible in rat lung using Hp (129) Xe. Magn Reson Med 76:566-576, 2016. © 2015 Wiley Periodicals, Inc.

Hyperpolarized 3He and 129Xe magnetic resonance imaging apparent diffusion coefficients: physiological relevance in older never- and ex-smokers.

Noble gas pulmonary magnetic resonance imaging (MRI) is transitioning away from (3)He to (129)Xe gas, but the physiological/clinical relevance of (129)Xe apparent diffusion coefficient (ADC) parenchyma measurements is not well understood. Therefore, our objective was to generate (129)Xe MRI ADC for comparison with (3)He ADC and with well-established measurements of alveolar structure and function in older never-smokers and ex-smokers with chronic obstructive pulmonary disease (COPD). In four never-smokers and 10 COPD ex-smokers, (3)He (b = 1.6 sec/cm(2)) and (129)Xe (b = 12, 20, and 30 sec/cm(2)) ADC, computed tomography (CT) density-threshold measurements, and the diffusing capacity for carbon monoxide (DLCO) were measured. To understand regional differences, the anterior-posterior (APG) and superior-inferior (∆SI) ADC differences were evaluated. Compared to never-smokers, COPD ex-smokers showed greater (3)He ADC (P = 0.006), (129)Xe ADCb12 (P = 0.006), and ADCb20 (P = 0.006), but not for ADCb30 (P > 0.05). Never-smokers and COPD ex-smokers had significantly different APG for (3)He ADC (P = 0.02), (129)Xe ADCb12 (P = 0.006), and ADCb20 (P = 0.01), but not for ADCb30 (P > 0.05). ∆SI for never- and ex-smokers was significantly different for (3)He ADC (P = 0.046), but not for (129)Xe ADC (P > 0.05). There were strong correlations for DLCO with (3)He ADC and (129)Xe ADCb12 (both r = -0.95, P < 0.05); in a multivariate model (129)Xe ADCb12 was the only significant predictor of DLCO (P = 0.049). For COPD ex-smokers, CT relative area <-950 HU (RA950) correlated with (3)He ADC (r = 0.90, P = 0.008) and (129)Xe ADCb12 (r = 0.85, P = 0.03). In conclusion, while (129)Xe ADCb30 may be appropriate for evaluating subclinical or mild emphysema, in this small group of never-smokers and ex-smokers with moderate-to-severe emphysema, (129)Xe ADCb12 provided a physiologically appropriate estimate of gas exchange abnormalities and alveolar microstructure.

Detection of radiation induced lung injury in rats using dynamic hyperpolarized (129)Xe magnetic resonance spectroscopy.

PURPOSE: Radiation induced lung injury (RILI) is a common side effect for patients undergoing thoracic radiation therapy (RT). RILI can lead to temporary or permanent loss of lung function and in extreme cases, death. Combining functional lung imaging information with conventional radiation treatment plans may lead to more desirable treatment plans that reduce lung toxicity and improve the quality of life for lung cancer survivors. Magnetic Resonance Imaging of the lung following inhalation of hyperpolarized(129)Xe may provide a useful nonionizing approach for probing changes in lung function and structure associated with RILI before, during, or after RT (early and late time-points). METHODS: In this study, dynamic(129)Xe MR spectroscopy was used to measure whole-lung gas transfer time constants for lung tissue and red blood cells (RBC), respectively (TTr_tissue and TTr_RBC) in groups of rats at two weeks and six weeks following 14 Gy whole-lung exposure to radiation from a (60)Co source. A separate group of six healthy age-matched rats served as a control group. RESULTS: TTr_tissue values at two weeks post-irradiation (51.6 ± 6.8 ms) were found to be significantly elevated (p < 0.05) with respect to the healthy control group (37.2 ± 4.8 ms). TTr_RBC did not show any significant changes between groups. TTr_tissue was strongly correlated with TTr_RBC in the control group (r = 0.9601 p < 0.05) and uncorrelated in the irradiated groups. Measurements of arterial partial pressure of oxygen obtained by arterial blood sampling were found to be significantly decreased (p < 0.05) in the two-week group (54.2 ± 12.3 mm Hg) compared to those from a representative control group (85.0 ± 10.0 mm Hg). Histology of a separate group of similarly irradiated animals confirmed the presence of inflammation due to radiation exposure with alveolar wall thicknesses that were significantly different (p < 0.05). At six weeks post-irradiation, TTr_tissue returned to values (35.6 ± 9.6 ms) that were not significantly different from baseline. CONCLUSIONS: Whole-lung tissue transfer time constants for(129)Xe (TTr_tissue) can be used to detect the early phase of RILI in a rat model involving 14 Gy thoracic (60)Co exposure as early as two weeks post-irradiation. This knowledge combined with more sophisticated models of gas exchange and imaging techniques, may allow functional lung avoidance radiation therapy planning to be achievable, providing more beneficial treatment plans and improved quality of life for recovering lung cancer patients.

Mapping metabolic changes associated with early Radiation Induced Lung Injury post conformal radiotherapy using hyperpolarized ¹³C-pyruvate Magnetic Resonance Spectroscopic Imaging.

PURPOSE: Radiation Pneumonitis (RP) limits radiotherapy. Detection of early metabolic changes in the lungs associated with RP may provide an opportunity to adjust treatment before substantial toxicities occur. In this work, regional lactate-to-pyruvate signal ratio (lac/pyr) was quantified in rat lungs and heart following administration of hyperpolarized (13)C-pyruvate magnetic resonance imaging (MRI) at day 5, 10, 15 and 25-post conformal radiotherapy. These results were also compared to histology and blood analyses. METHODS: The lower right lungs of 12 Sprague Dawley rats were irradiated in 2 fractions with a total dose of 18.5 Gy using a modified micro-CT system. Regional lactate and pyruvate data were acquired from three irradiated and three age-matched healthy rats at each time point on days 5, 10, 15 and 25-post radiotherapy. Arterial blood was collected from each animal prior to the (13)C-pyruvate injection and was analyzed for blood lactate concentration and arterial oxygen concentration (paO2). Macrophage count was computed from the histology of all rat lungs. RESULTS: A significant increase in lac/pyr was observed in both right and left lungs of the irradiated cohort compared to the healthy cohort for all time points. No increase in lac/pyr was observed in the hearts of the irradiated cohort compared to the hearts of the healthy cohorts. Blood lactate concentration and paO2 did not show a significant change between the irradiated and the healthy cohorts. Macrophage count in both right and left lungs was elevated for the irradiated cohort compared to the healthy cohort. CONCLUSIONS: Metabolic changes associated with RP may be mapped as early as five days post conformal radiotherapy. Over the small sample size in each cohort, elevated macrophage count, consistent with early phase of inflammation was highly correlated to increases in lac/pyr in both the irradiated and unirradiated lungs. Further experiments with larger sample size may improve the confidence of this finding.

Comparison of hyperpolarized (3)He and (129)Xe MRI for the measurement of absolute ventilated lung volume in rats.

PURPOSE: MRI using hyperpolarized noble gases, (3)He and (129)Xe, provides noninvasive assessments of lung structure and function. Previous work demonstrated that absolute ventilated lung volumes (aVLV) measured in rats using hyperpolarized (3)He agree well with micro-CT. METHODS: In this work, aVLV measurements were performed in rats using hyperpolarized (129)Xe MRI and compared with hyperpolarized (3)He measurements of aVLV under matched ventilation conditions. Whole-lung compliance was also determined. Partial volume, apparent diffusion coefficient, and effective transverse relaxation time corrections were applied during postprocessing to reduce bias between methods. RESULTS: Mean apparent diffusion coefficient of the trachea was 0.83 ± 0.09 cm(2)/s and 0.067 ± 0.011 cm(2)/s for (3)He and (129)Xe, respectively. Mean apparent diffusion coefficient of parenchyma was 0.21 ± 0.07 cm(2)/s and 0.027 ± 0.008 cm(2)/s for (3)He and (129)Xe, respectively. Mean transverse relaxation time values were 1.57 ± 0.25 ms and 2.80 ± 0.25 ms for (3)He and (129)Xe, respectively, in a model trachea and 3.18 ± 1.00 ms and 4.88 ± 0.60 ms for (3)He and (129)Xe, respectively, for lung parenchyma. Mean aVLV values were 7.07 ± 0.67 mL and 6.99 ± 1.00 mL at 14 cmH2O and 4.88 ± 0.71 mL and 5.36 ± 0.76 mL at 10 cmH2O obtained with (3)He and (129)Xe, respectively, demonstrating good agreement between (129)Xe and (3)He. CONCLUSIONS: (129)Xe offers an important alternative to (3)He for hyperpolarized gas MRI of aVLV in rats.

Lung morphometry using hyperpolarized (129) Xe apparent diffusion coefficient anisotropy in chronic obstructive pulmonary disease.

PURPOSE: The goal of this work was to investigate lung morphological changes associated with chronic obstructive pulmonary disease (COPD) using hyperpolarized (129) Xe diffusion-weighted MRI. METHODS: Hyperpolarized (129) Xe MRI was performed at three different nonzero diffusion sensitizations (b-value = 12, 20, and 30 s/cm(2) ) in the lungs of four subjects with COPD and four healthy volunteers. The image signal intensities were fit as a function of b-value to obtain anisotropic diffusion coefficient maps for all subjects. The image signal intensities were also fit to a morphological model allowing extraction of length scales associated with the terminal airways: external radius (R), internal radius (r), mean airspace chord length (Lm ), and depth of alveolar sleeve (h). RESULTS: Longitudinal (DL ) and transverse (DT ) anisotropic diffusion coefficients were both significantly increased (both P= 0.004) in the COPD subjects (0.102 ± 0.02 cm(2) /s and 0.072 ± 0.02 cm(2) /s, respectively) compared with the healthy subjects (0.083 ± 0.011 cm(2) /s and 0.046 ± 0.017 cm(2) /s, respectively). Significant morphological differences were observed between the COPD subjects and healthy volunteers, specifically decreases in h (68 ± 36 µm vs. 95 ± 710 µm, respectively, P = 0.019) and increases in Lm (352 ± 57 µm vs. 253 ± 37 µm, respectively, P = 0.002) consistent with values obtained previously using hyperpolarized (3) He MRI in similar subjects. CONCLUSIONS: Diffusion-weighted hyperpolarized (129) Xe MRI is a promising technique for mapping changes in human lung morphology and may be useful for early detection of emphysema associated with COPD.

Pulmonary ventilation visualized using hyperpolarized helium-3 and xenon-129 magnetic resonance imaging: differences in COPD and relationship to emphysema.

In subjects with chronic obstructive pulmonary disease (COPD), hyperpolarized xenon-129 ((129)Xe) magnetic resonance imaging (MRI) reveals significantly greater ventilation defects than hyperpolarized helium-3 ((3)He) MRI. The physiological and/or morphological determinants of ventilation defects and the differences observed between hyperpolarized (3)He and (129)Xe MRI are not yet understood. Here we aimed to determine the structural basis for the differences in ventilation observed between (3)He and (129)Xe MRI in subjects with COPD using apparent diffusion coefficients (ADC) and computed tomography (CT). Ten COPD ex-smokers provided written, informed consent and underwent MRI, CT, spirometry, and plethysmography. (3)He and (129)Xe MRI ventilation volume was generated using semiautomated segmentation, and ADC maps were registered to generate ADC values for lung regions of interest ventilated by both gases (ADCHX) and by (3)He gas only (ADCHO). CT wall area percentage and the lowest 15th percentile point of the CT lung density histogram (HU15%) were also evaluated. For lung regions accessed by (3)He gas only, mean (3)He ADCHO was significantly greater than for regions accessed by both gases (ADCHO = 0.503 ± 0.119 cm(2)/s, ADCHX = 0.470 ± 0.125 cm(2)/s, P < 0.0001). The difference between (3)He and (129)Xe ventilation volume was significantly correlated with CT HU15% (r = -65, P = 0.04) and (3)He ADCHO (r = 0.70, P = 0.02), but not CT wall area percentage (r = -0.34, P = 0.33). In conclusion, in this small study in COPD subjects, we observed significantly decreased (129)Xe MRI ventilation compared with (3)He MRI, and these regions of decreased (129)Xe ventilation were spatially and significantly correlated with regions of increased pulmonary emphysema, but not airway wall thickness.

Measurement of 129Xe gas apparent diffusion coefficient anisotropy in an elastase-instilled rat model of emphysema.

Hyperpolarized noble gas ((3)He and (129)Xe) apparent diffusion coefficient (ADC) measurements have shown remarkable sensitivity to microstructural (i.e., alveolar) changes in the lung, particularly emphysema. The ADC of hyperpolarized noble gases depends strongly on the diffusion time (Δ), and (3)He ADC has been shown to be anisotropic for Δ ranging from a few milliseconds down to a few hundred microseconds. In this study, the anisotropic nature of (129)Xe diffusion and its dependence on Δ were investigated both numerically, in a budded cylinder model, and in vivo, in an elastase-instilled rat model of emphysema. Whole lung longitudinal ADC (D(L)) and transverse ADC (D(T)) were measured for Δ = 6, 50, and 100 ms at 73.5 mT, and correlated with measurements of the mean linear intercept (L(m)) obtained from lung histology. A significant increase (P = 0.0021) in D(T) was measured for Δ = 6 ms between the sham (0.0021 ± 0.0005 cm(2)/s) and elastase-instilled (0.005 ± 0.001 cm(2)/s) cohorts, and a strong correlation was measured between D(T) (Δ = 6 ms) and L(m), with a Pearson's correlation coefficient of 0.90. This study confirms that (129)Xe D(T) increases correlate with alveolar space enlargement due to elastase instillation in rats.

Hyperpolarized 3He and 129Xe MR imaging in healthy volunteers and patients with chronic obstructive pulmonary disease.

PURPOSE: To quantitatively compare hyperpolarized helium 3 (3He) and xenon 129 (129Xe) magnetic resonance (MR) images obtained within 5 minutes in healthy volunteers and patients with chronic obstructive pulmonary disease (COPD) and to evaluate the correlations between 3He and 129Xe MR imaging measurements and those from spirometry and plethysmography. MATERIALS AND METHODS: This study was approved by an ethics board and compliant with HIPAA. Written informed consent was obtained from all subjects. Eight healthy volunteers and 10 patients with COPD underwent MR imaging, spirometry, and plethysmography. Ventilation defect percentages (VDPs) at 3He and 129Xe imaging were obtained by using semiautomated segmentation. Apparent diffusion coefficients (ADCs) were calculated from 3He (b=1.6 sec/cm2) and 129Xe (b=12 sec/cm2) diffusion-weighted images. VDPs at hyperpolarized 3He and 129Xe imaging were compared with a two-tailed Wilcoxon signed rank test and analysis of variance; Pearson correlation coefficients were used to evaluate the relationships among measurements. RESULTS: 129Xe VDP was significantly greater than 3He VDP for patients with COPD (P<.0001) but not for healthy volunteers (P=.35), although 3He and 129Xe VDPs showed a significant correlation for all subjects (r=0.91, P<.0001). The forced expiratory volume in 1 second (FEV1) showed a similar and significant correlation with 3He VDP (r=-0.84, P<.0001) and 129Xe VDP (r=-0.89, P<.0001), although the correlation between the FEV1/forced vital capacity (FVC) ratio and 129Xe VDP (r=-0.95, P<.0001) was significantly greater (P=.01) than that for FEV1/FVC and 3He VDP (r=-0.84, P<.0001). A significant correlation was also observed for 3He and 129Xe ADC (r=0.97, P<.0001); 129Xe ADC was significantly correlated with diffusing capacity of lung for carbon monoxide (r=-0.79, P=.03) and computed tomographic emphysema measurements (areas with attenuation values in the 15th percentile: r=-0.91, P=.0003; relative areas with attenuation values of less than -950 HU: r=0.87, P=.001). CONCLUSION: In patients with COPD, the VDP obtained with hyperpolarized 29Xe MR imaging was significantly greater than that with 3He MR imaging, suggesting incomplete or delayed filling of lung regions that may be related to the different properties of 129Xe gas and physiologic and/or anatomic abnormalities in COPD.

Hyperpolarized 129Xe magnetic resonance imaging: tolerability in healthy volunteers and subjects with pulmonary disease.

RATIONALE AND OBJECTIVES: The objective of this study was to evaluate the tolerability of hyperpolarized (129)Xe gas inhaled from functional residual capacity and magnetic resonance imaging in healthy subjects and those with pulmonary disease. MATERIALS AND METHODS: Twelve healthy volunteers (mean age, 59 ± 17 years), seven subjects with asthma (mean age, 47 ± 7 years), 10 subjects with chronic obstructive pulmonary disease (mean age, 74 ± 4 years), three subjects with cystic fibrosis (mean age, 27 ± 10 years), and a single subject with radiation-induced lung injury (age, 66 years) were enrolled and evaluated over 43 visits with 136 anoxic inhalations of 500 mL (129)Xe gas mixed with 500 mL (4)He gas. Oxygen saturation and heart rate were monitored during the breath-hold and imaging; subjects were queried for adverse events (AEs) before and immediately following gas inhalation and for 24 hours after the last dose. RESULTS: No subjects withdrew from the study or reported serious, hypoxic, or severe AEs. Over the course of 136 dose administrations, two mild AEs (1%) were reported in two different subjects (two of 33 [6%]). One of these AEs (light-headedness) was temporally related and judged as possibly related to (129)Xe administration and resolved without treatment within 2 minutes. Statistically significant but clinically insignificant changes in oxygen saturation and heart rate were observed after inhalation (P < .001), and both resolved 1 minute later, with no difference between subject groups. CONCLUSIONS: Inhalation of hyperpolarized (129)Xe gas and subsequent magnetic resonance imaging were well tolerated in healthy subjects and ambulatory subjects with obstructive and restrictive pulmonary disease.

Regional ventilation mapping of the rat lung using hyperpolarized ¹²9Xe magnetic resonance imaging.

Lung ventilation was mapped in seven healthy male Sprague-Dawley rats (433 ± 24 g) using hyperpolarized ¹²9Xe magnetic resonance imaging (MRI) at 3.0 T, and validated with hyperpolarized ³He MRI under similar ventilator conditions. Ventilation maps were obtained using flip angle variation for offset of RF and relaxation (FAVOR) which is a multiple breath imaging technique that extracts the fractional ventilation parameter, r, on a pixel-by-pixel basis from the dynamic signal enhancement. r is defined as the fractional refreshment of gas per breath. Under the ventilator conditions used in this work, whole-lung measurements of fractional ventilation obtained using hyperpolarized ¹²9Xe were not significantly different from those obtained using hyperpolarized ³He (p = 0.8125 by a Wilcoxon matched pairs test). Fractional ventilation gradients calculated in the superior/inferior (S/I) and anterior/posterior (A/P) directions obtained using hyperpolarized ¹²9Xe were not significantly different from those obtained using hyperpolarized ³He (p = 0.9375 and p = 0.1563, for the S/I and A/P directions, respectively). Following baseline fractional ventilation measurements, one representative rat was challenged with methacholine and fractional ventilation measurements were performed over a time course of 10 min. A reduction and subsequent recovery in whole-lung r values were detected using the FAVOR method.

Mapping of (3) He apparent diffusion coefficient anisotropy at sub-millisecond diffusion times in an elastase-instilled rat model of emphysema.

Hyperpolarized (3) He gas can provide detailed anatomical maps of the macroscopic airways in the lungs (i.e., ventilation) as well as insight into the lung microstructure through the apparent diffusion coefficient. In particular, the apparent diffusion coefficient of (3) He in the lung exhibits anisotropic effects that depend on diffusion time (δ), and it has been shown to be extraordinarily sensitive to enlargement in terminal airways and alveoli associated with emphysema. In this study, the anisotropic nature of the (3) He apparent diffusion coefficient is studied in a rat model of emphysema, based on elastase instillation, specifically for δ values less than one millisecond. Longitudinal (D(L) ) and transverse (D(T) ) diffusion coefficients were mapped at δ = 360 µs and δ = 800 µs based on a cylinder model of lung structure and correlated with histological measurement of alveolar damage based on mean linear intercept (L(m) ). Whole-lung mean D(T) measured at δ = 360 µs in the elastase-instilled rat lungs (0.14 ± 0.09 cm(2) /s) demonstrated the most significant increase (p = 0.00195) compared to the sham-instilled cohort (0.06 ± 0.06 cm(2) /s) and had a strong linear correlation with L(m) (Pearson's correlation coefficient of 0.9). These results suggest that measurement of (3) He apparent diffusion coefficient anisotropy, specifically D(T) , can provide a sensitive indicator of emphysema, particularly at very short diffusion times (δ = 360 µs).